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1.
Bioorg Med Chem Lett ; 21(11): 3411-6, 2011 Jun 01.
Article in English | MEDLINE | ID: mdl-21515049

ABSTRACT

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines. This compound showed prolonged Hsp90-inhibitory activity at least 24 h post-administration, consistent with elevated and prolonged exposure in the tumor.


Subject(s)
Antineoplastic Agents/pharmacology , Biomarkers/metabolism , Drug Design , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Lactams, Macrocyclic/chemical synthesis , Lactams, Macrocyclic/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Cell Line, Tumor , Cell Proliferation/drug effects , Crystallography, X-Ray , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/chemistry , Fluorescent Dyes/pharmacology , Humans , Inhibitory Concentration 50 , Lactams, Macrocyclic/chemistry , Models, Molecular , Molecular Structure , ortho-Aminobenzoates/chemical synthesis , ortho-Aminobenzoates/chemistry , ortho-Aminobenzoates/pharmacology
2.
Bioorg Med Chem Lett ; 21(8): 2278-82, 2011 Apr 15.
Article in English | MEDLINE | ID: mdl-21420297

ABSTRACT

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.


Subject(s)
Antineoplastic Agents/chemistry , Benzamides/chemistry , HSP90 Heat-Shock Proteins/antagonists & inhibitors , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/pharmacology , Benzamides/chemical synthesis , Benzamides/pharmacology , Binding Sites , Cell Line, Tumor , Cell Proliferation , Computer Simulation , Crystallography, X-Ray , Drug Design , HSP90 Heat-Shock Proteins/metabolism , Humans , Protein Binding , Structure-Activity Relationship
3.
Eur J Med Chem ; 45(4): 1379-86, 2010 Apr.
Article in English | MEDLINE | ID: mdl-20074837

ABSTRACT

A series of 8,9-dimethoxy-5-(2-aminoalkoxy-pyridin-3-yl)-benzo[c][2,7]naphthyridin-4-ylamine-based inhibitors of 3-phosphoinositide-dependent kinase-1 (PDK-1) has been identified. Several examples appear to be potent and relatively selective inhibitors of PDK-1 over the related AGC kinases PKA, PKB/AKT, and p70S6K. The introduction of a stereochemical center beside the amino substituent on the aminoalkoxy-side chain had little effect upon the inhibitory activity against these enzymes, and X-ray crystallographic analyses of a representative pair of enantiomeric inhibitors bound to the active site of PDK-1 revealed comparable binding modes for each enantiomer.


Subject(s)
Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/antagonists & inhibitors , Pyridines/pharmacology , 3-Phosphoinositide-Dependent Protein Kinases , Crystallography, X-Ray , Hydrogen Bonding , Models, Molecular , Molecular Structure , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Static Electricity , Structure-Activity Relationship
4.
Bioorg Med Chem Lett ; 19(9): 2461-3, 2009 May 01.
Article in English | MEDLINE | ID: mdl-19345579

ABSTRACT

A series of 4-indolylamino-5-phenyl-3-pyridinecarbonitrile inhibitors of PKCtheta were synthesized as potential anti-inflammatory agents. The effects of specific substitution on the 5-phenyl moiety and variations of the positional isomers of the 4-indolylamino substituent were explored. This study led to the discovery of compound 12d, which had an IC(50) value of 18nM for the inhibition of PKCtheta.


Subject(s)
Isoenzymes/antagonists & inhibitors , Protein Kinase C/antagonists & inhibitors , Protein Kinase Inhibitors/chemical synthesis , Pyridines/chemical synthesis , Adenosine Triphosphate/chemistry , Animals , Anti-Inflammatory Agents/pharmacology , Chemistry, Pharmaceutical/methods , Drug Design , Humans , Inhibitory Concentration 50 , Isoenzymes/chemistry , Mice , Models, Chemical , Molecular Structure , Protein Isoforms , Protein Kinase C/chemistry , Protein Kinase C-theta , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Structure-Activity Relationship
5.
Bioorg Med Chem ; 15(11): 3635-48, 2007 Jun 01.
Article in English | MEDLINE | ID: mdl-17416531

ABSTRACT

A series of 4-dimethylamino-but-2-enoic acid [4-(3,6-dioxo-cyclohexa-1,4-dienylamino)-7-ethoxy-quinazolin-6-yl]-amide derivatives were prepared. These compounds have two independent reactive centers and were designed to function as dual irreversible inhibitors of the kinase domains of both Epidermal Growth Factor Receptor (EGFR) and Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) where each reactive center targets a different, non-conserved, cysteine residue located in the ATP binding pocket of these enzymes. The compounds contain a 6-(4-(dimethylamino) crotonamide) Michael acceptor group that targets Cys-773 in EGFR and a 4-(amino-[1,4]benzoquinone) moiety that targets Cys-1045 in VEGFR-2. In vitro studies indicated that most of these compounds are relatively potent inhibitors of each enzyme. These inhibitors were compared with reference compounds that lack one or both of the reactive centers. The relative dependence of the IC(50) values on the concentration of ATP used in the assays suggests that these compounds appear to function as irreversible inhibitors of each kinase.


Subject(s)
ErbB Receptors/antagonists & inhibitors , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/pharmacology , Quinazolines/chemistry , Quinazolines/pharmacology , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate/chemistry , Adenosine Triphosphate/metabolism , Binding Sites , Biological Assay , Cells, Cultured , ErbB Receptors/chemistry , ErbB Receptors/metabolism , Humans , Inhibitory Concentration 50 , Models, Molecular , Molecular Structure , Protein Conformation/drug effects , Protein Kinase Inhibitors/chemical synthesis , Quinazolines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolism
6.
J Med Chem ; 48(24): 7560-81, 2005 Dec 01.
Article in English | MEDLINE | ID: mdl-16302797

ABSTRACT

A series of 2-(quinazolin-4-ylamino)-[1,4] benzoquinone derivatives that function as potent covalent-binding, irreversible inhibitors of the kinase domain of vascular endothelial growth factor receptor-2 (VEGFR-2) has been prepared by ceric ammonium nitrate oxidation of substituted (2,5-dimethoxyphenyl)(6,7-disubstituted-quinazolin-4-yl)amines and by displacement of the chlorine atom of substituted 2-chloro-5-(6,7-disubstituted-quinazolin-4-ylamino)-[1,4]benzoquinones with various amines, anilines, phenols, and alcohols. Enzyme studies were conducted in the absence and presence of glutathione and plasma. Several of the compounds inhibit VEGF-stimulated autophosphorylation in intact cells. Kinetic experiments were performed to study the reactivity of selected inhibitors toward glutathione. Reactivities correlated with LUMO energies calculated as averages of those of individual conformers weighted by the Boltzmann distribution. These results and molecular modeling were used to rationalize the biological observations. The compounds behave as non-ATP-competitive inhibitors. Unequivocal evidence, from mass spectral studies, indicates that these inhibitors form a covalent interaction with Cys-1045. One member of this series displays antitumor activity in an in vivo model.


Subject(s)
Angiogenesis Inhibitors/chemical synthesis , Benzoquinones/chemical synthesis , Quinazolines/chemical synthesis , Vascular Endothelial Growth Factor Receptor-2/antagonists & inhibitors , Adenosine Triphosphate/metabolism , Angiogenesis Inhibitors/chemistry , Angiogenesis Inhibitors/pharmacology , Animals , Benzoquinones/chemistry , Benzoquinones/pharmacology , Binding Sites , Cell Line , Female , Glutathione/chemistry , Humans , Kinetics , Mice , Mice, Nude , Models, Molecular , Molecular Conformation , Phosphorylation , Protein Binding , Protein Structure, Tertiary , Quantum Theory , Quinazolines/chemistry , Quinazolines/pharmacology , Spectrometry, Mass, Electrospray Ionization , Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization , Structure-Activity Relationship , Vascular Endothelial Growth Factor Receptor-2/chemistry , Vascular Endothelial Growth Factor Receptor-2/metabolism , Xenograft Model Antitumor Assays
7.
J Med Chem ; 47(19): 4741-54, 2004 Sep 09.
Article in English | MEDLINE | ID: mdl-15341489

ABSTRACT

A growing body of evidence suggests that CRF(1) receptor antagonism offers considerable therapeutic potential in the treatment of diseases resulting from elevated levels of CRF, such as anxiety and depression. A series of novel 1,2,3,7-tetrahydro-6H-purin-6-one and 3,7-dihydro-1H-purine-2,6-dione derivatives was synthesized and evaluated as corticotropin releasing factor-1 (CRF(1)) receptor antagonists. Compounds within this series, represented by compound 12d (IC(50) = 5.4 nM), were found to be highly potent CRF(1) receptor antagonists. In addition, compounds 12d and 12j were determined to be selective CRF(1) antagonists. The synthesis, structure-activity relationships and pharmacokinetic properties of compounds within this series is presented.


Subject(s)
Drug Design , Purines/chemistry , Purines/pharmacology , Receptors, Corticotropin-Releasing Hormone/antagonists & inhibitors , Animals , Cell Line , Cyclic AMP/metabolism , Humans , Hydroxylation , Inhibitory Concentration 50 , Molecular Structure , Purines/chemical synthesis , Rats , Receptors, Corticotropin-Releasing Hormone/metabolism , Structure-Activity Relationship
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